US4769181A - 1,25-dihydroxyvitamin D2 compounds - Google Patents
1,25-dihydroxyvitamin D2 compounds Download PDFInfo
- Publication number
- US4769181A US4769181A US06/549,047 US54904783A US4769181A US 4769181 A US4769181 A US 4769181A US 54904783 A US54904783 A US 54904783A US 4769181 A US4769181 A US 4769181A
- Authority
- US
- United States
- Prior art keywords
- compounds
- dihydroxyvitamin
- trans
- vitamin
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0042—Nitrogen only
Definitions
- This invention relates to the preparation of hydroxylated compounds of the vitamin D 2 series.
- this invention relates to a process for the synthesis of 1 ⁇ ,25-dihydroxyvitamin D 2 and 1 ⁇ ,25-dihydroxyvitamin D 2 , of the corresponding 5,6-trans-isomers, and the C-24 epimers of these compounds.
- Vitamin D 3 the natural form of the vitamin produced in skin, is known to be hydroxylated in vivo to 25-hydroxyvitamin D 3 and then to 1 ⁇ ,25-dihydroxyvitamin D 3 , the latter compound being generally regarded as the tissue-active hormonal form of the vitamin.
- vitamin D 2 which is commonly used as a food additive or vitamin D supplement, undergoes the same hydroxylation sequence in vivo to form 25-hydroxyvitamin D 2 (25-OH-D 2 ) and 1 ⁇ ,25-dihydroxyvitamin D 2 (1 ⁇ ,25-(OH) 2 D 2 ), the latter being essentially as active as 1 ⁇ ,25-dihydroxyvitamin D 3 in humans and other mammals.
- a convenient starting material for this process is 25-hydroxyvitamin D 2 (structure 1, 24S-sterochemistry), or its 24R-epimer, 25-hydroxy-24-epi-vitamin D 2 (structure 1, 24R-stereochemistry), or a mixture of both compounds.
- 25-hydroxyvitamin D 2 having the natural 24S-configuration, and its 24R-epimer ia a known compound.
- the 24R-epimer has been prepared previously (DeLuca, U.S. Pat. No. 3,585,221 and DeLuca et al. U.S. patent application Ser. No. 420,191, filed Sept. 20, 1982).
- the first step of the process comprises conversion of starting material of structure 1 to the corresponding C-3-tosylate (structure 2) using conventional tosylation procedures, and subsequent solvolysis of the tosylate according to the procedures of DeLuca et al., (U.S. Pat. No. 4,195,027) to obtain the cyclovitamin D derivative of structure 3.
- This intermediate is then subjected to allylic hydroxylation with SeO 2 /t-butyl hydroperoxide, to obtain the 1-hydroxy-cyclovitamin D 2 derivatives.
- This allylic hydroxylation process yields the 1 ⁇ -hydroxy-cyclovitamin D product represented by structure 4 as expected, but also, in this case, the corresponding 1 ⁇ -hydroxy isomer of structure 5.
- isomer separation can be accomplished by conventional methods, e.g. high performance chromatography, but for the purposes of the present process, isomer separation is not required at this stage.
- compounds 10a, 10b, 11a, 11b, 12a and 12b were recovered by chromatographic separation of the reaction mixture.
- the 5,6-trans compounds 13a and 13b can also be isolated from the solvolysis mixture by careful chromatography, but when their abundance in the mixture is low so as to make recovery tedious and time-consuming, it is generally more convenient to obtain them from the cis-isomers 11a and 11b by 5,6-double bond isomerization.
- hydroxy-protected derivatives are for example the acylated compounds represented by general formulae 15 and 16 below, ##STR4## wherein each of R 1 , R 2 , and R 3 is selected from the group onsisting of hydrogen and acyl, except that at least one of R 1 , R 2 and R 3 must be acyl.
- ⁇ acyl ⁇ refers to an aliphatic acyl group (alkanoyl group) of from 1 to 6 carbons, in all possible isomeric forms (e.g.
- acyl group such as benzoyl, or the methyl- halo- or nitro-substituted benzoyl groups, or a dicarboxylic acyl group of from 2 to 6 atoms chain length, i.e. acyl groups of the type ROOC(CH 2 ) n CO--, or ROOCCH 2 --O--CH 2 CO--, where n has values between 0 and 4 inclusive, and R is hydrogen or an alkyl radical.
- dicarboxylic acyl groups are oxalyl, malonyl, succinoyl, glutaryl, adipyl and diglycolyl.
- ⁇ alkyl ⁇ refers to a lower alkyl group of 1 to 6 carbons in all possible isomeric forms, e.g. methyl, ethyl, propyl, isopropyl, isobutyl, pentyl, etc.
- acyl derivatives are conveniently prepared from the free hydroxy compounds (or, if desired, from the C-3-monoacylated intermediates of structure 6, 7, 8 or 9) by conventional acylation procedures, i.e. treatment of any of the hydroxyvitamin D 2 products with an acyl chloride, or acyl anhydride in a suitable solvent such as pyridine, or alkylpyridine.
- acylating agent i.e. treatment of any of the hydroxyvitamin D 2 products with an acyl chloride, or acyl anhydride in a suitable solvent such as pyridine, or alkylpyridine.
- the 1,3-diacetate can be further acylated at C-25 with a different acyl group; e.g. treatment with benzoyl chloride or succinic anhydride would provide the 1,3-diacetyl-25-benzoyl- or ⁇ ,3-diacetyl-25-succinoyl-derivative, respectively.
- a 1,3,25-triacyl derivative can be selectively hydrolyzed in mild base to provide the 1,3-dihydroxy-25-acyl compound, the free hydroxy groups of which can be reacylated, if desired, with different acyl groups.
- a 1,3-diacyl derivative can be subjected to partial acyl hydrolysis to obtain the 1-O-acyl and the 3-O-acyl-compounds, which in turn can be reacylated with different acyl groups.
- Like treatment of the other hydroxyvitamin D 2 products (10, 11, 12 or 13) provides the corresponding desired acyl derivatives of structures 15 or 16.
- the novel compounds of this invention exhibit pronounced vitamin D-like activity, and thus represent desirable substitutes for the known vitamin D 2 or D 3 metabolites in many therapeutic or veterinary applications.
- Particularly preferred in this regard are the products of structure 13a and 13b. These compounds exhibit high binding affinity for the intestinal receptor protein, and since binding affinity generally correlates with high in vivo activity, these compounds can be expected to be especially useful for the treatment of diseases related to mineral imbalance.
- novel compounds may be used for correcting or improving a variety of calcium and phosphate imbalance conditions resulting from a variety of diseases, such as vitamin D-resistant rickets, osteomalacia, hypoparathyroidism, pseudohypoparathyroidism, osteoporosis, Paget's disease, and similar bone and mineral-related disease states well known to the medical practice.
- diseases such as vitamin D-resistant rickets, osteomalacia, hypoparathyroidism, pseudohypoparathyroidism, osteoporosis, Paget's disease, and similar bone and mineral-related disease states well known to the medical practice.
- the compounds can also be used for the treatment of mineral imbalance conditions in animals, such as the milk fever condition, poultry or swine leg weakness, or for improving egg shell quality of fowl.
- these compounds may be administered orally or by injection or infusion in any form convenient or appropriate to the method of administration selected.
- the compounds may be formulated with any therapeutically acceptable and innocuous carrier, in the form of pills, tablets or gelatin capsules for oral administration, or they may be formulated as solutions, emulsions, dispersions or suspensions in innocuous solvents and oils, and such formulations may contain also other therapeutically active and beneficial constituents, such as other vitamins, salts, sugars, hormones, etc. as may be appropriate to the specific application.
- the novel compounds may be administered singly or as mixtures, e.g.
- the compounds of this invention are administered in dosage amounts of between about 0.5 to 100 ⁇ m per day, it being understood, of course, that the specific dosage administered in any given case will be adjusted in accordance with the specific compound administered, the disease to be treated, the condition of the subject and other relevant medical facts that may modify the activity of the drug or the response of the subject, as is well-known by those skilled in the art.
- Freshly recrystallized p-toluenesulfonly chloride (50 mg) was added to a solution of 33 mg (24R/S)-25-hydroxyvitamin D 2 (1) in dry pyridine (300 ⁇ l). The reaction mixture was allowed to stand for 30 hours at 4° C., poured into ice/saturated NaHCO 3 with stirring and extracted with benzene. The combined extracts were washed with NaHCO 3 , water, aqueous CuSO 4 solution, water, then dried over MgSO 4 . Removal of solvent under reduced pressure gave a crude tosylate (2), which can be used directly for the next reaction.
- the 5,6-cis form of the 1,25-dihydroxyvitamin D compounds thus obtained can be converted to the trans compounds by treatment with iodine.
- compound 11a upon treatment with iodine under the above conditions provided a mixture of the 5,6-cis and 5,6-trans-isomer (11a, 13a) which when separated by HPLC (Zorbax-Sil, 9.6 ⁇ 25 cm, 10% 2-propanol/hexane) gave 13a in pure form, and treatment of compound 11b, under the same conditions, gave the 5,6-trans compound 13b.
- HPLC Zorbax-Sil, 9.6 ⁇ 25 cm, 10% 2-propanol/hexane
- the cis to trans conversion may be used for preparing quantities of pure trans material.
- 1 ⁇ ,25-dihydroxyvitamin D 2 (11a): UV (EtOH) ⁇ max 263.5 nm, ⁇ min 227 nm; mass spectrum, m/e 428 (M + , 9), 410 (27), 392 (12), 352 (8), 334 (7), 269 (12), 251 (15), 152 (48), 135 (68), 134 (53), 59 (100).
- the C-22 aldehyde (1) is obtained by degradation of ergosterol acetate (in which the ring B diene system has been protected by Diels-Alder addition of 4-phenyl-1,2,4-triazoline-3,5-dione) according to the procedure of Barton et al. J. Chem. Soc. (c) 1968 (1971).
- the i-ether aldehyde (4) is obtained from stigmasterol by the method of U.S. Pat. No. 2,623,052.
- Grignard reagent is prepared from Mg (535 mg; 22.22 mmol) and ethyl bromide in ether (10 ml), and the virorously stirred solution is treated with sulfone A (6 g; 2.22 mmol) in benzene (6 ml). The precipitate formed is ground with a spatula, stirring is continued, and after 15 min the aldehyde (1) (2.0 g) is added in benzene (10 ml). The reaction mixture is stirred at room temperature for 24 hour, then poured into aqueous (NH 4 ) 2 SO 4 solution and extracted with benzene.
- Grignard reagent is prepared from Mg (75 mg, 3.1 mmol) and ethyl bromide in ether (10 ml).
- sulfone A 891 mg; 3.3 mmol
- benzene 5 ml
- a solution of aldehyde (4) 290 mg
- the reaction is continued for 2.5 h, then quenched with saturated (NH 4 ) 2 SO 4 solution (5 ml) and diluted with ether.
- the separated organic layer is washed with water, dried, and evaporated.
- the oily residue containing (5) is treated with acetic anhydride (2 ml) and pyridine (2 ml).
- the reaction mixture is allowed to stand for 24 hours, poured into water and extracted with benzene.
- the benzene extract is washed with an aqueous solution of CuSO 4 , water, dried, and evaporated.
- the crude product [the acetate of (5)] is dissolved in methanol saturated with Na 2 HPO.sub. 4 and sodium amalgam (5.65%, 8 g) is added.
- the reaction mixture is stirred at 4° C. for 16 hours.
- mercury is removed by filtration, methanol is evaporated, and water and benzene are added to dissolve the residue.
- the benzene layer is dried and evaporated.
- the reaction mixture is irradiated under argon atmosphere for 18 min with a mercury arc lamp (Hanovia SA-1) fitted with a Vycor filter.
- Grignard reagent is prepared from magnesium (240 mg) and methyl iodide in anhydrous ether (20 ml). To one-tenth of this solution (2 ml; 0.5M solution of CH 3 MgI) ketone (10) (16 mg; 0.04 mmol) in ether (2 ml) is added. The reaction mixture is stirred at room temperature for 2 hours under an inert atmosphere, then quenched with aqueous solution of NH 4 Cl, diluted with benzene and washed with water. The organic layer is separated, dried and evaporated.
- the crude product is first purified by silica gel column chromatography (elution with 20% ether in benzene) and the mixture of (11a) and (11b) (16 mg; 96%) thereby obtained is then repeatedly chromatographed on HPLC column using 2% 2-propanol in hexane as an eluent to separate the 24-stereoisomers, 24-epi-25-OH-D 2 (11b) and 25-OH-D 2 (11a). Chromatography and rechromatography of each stereoisomer yields 4 mg of (11b) (collected at 68 ml), 4 mg of (11a) (collected at 74 ml) and 7 mg of the mixture of both epimers. Treatment of 2 mg of the epimer mixture with excess acetic anhydride in pyridine solution at room temperature overnight followed by standard work-up yields the corresponding 3-O-acetates.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/549,047 US4769181A (en) | 1983-11-07 | 1983-11-07 | 1,25-dihydroxyvitamin D2 compounds |
AU33902/84A AU3390284A (en) | 1983-11-07 | 1984-08-20 | 1,25-dihydroxyvitamin d2 compounds and methods for their preparation |
PCT/US1984/001334 WO1985002189A1 (fr) | 1983-11-07 | 1984-08-20 | Composes de la 1,25-dihydroxy-vitamine d2 et leurs procedes de preparation |
BE0/213952A BE900979A (fr) | 1983-11-07 | 1984-11-05 | 1,25-dihydroxyvitamines d2 et procedes pour les preparer. |
GB08428031A GB2149408A (en) | 1983-11-07 | 1984-11-06 | 1,25-dihydroxyvitamin d2 compounds and methods for their preparation |
FR8416894A FR2554444B1 (fr) | 1983-11-07 | 1984-11-06 | 1,25-dihydroxyvitamines d2 et procedes pour les preparer |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/549,047 US4769181A (en) | 1983-11-07 | 1983-11-07 | 1,25-dihydroxyvitamin D2 compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
US4769181A true US4769181A (en) | 1988-09-06 |
Family
ID=24191451
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06/549,047 Expired - Lifetime US4769181A (en) | 1983-11-07 | 1983-11-07 | 1,25-dihydroxyvitamin D2 compounds |
Country Status (6)
Country | Link |
---|---|
US (1) | US4769181A (fr) |
AU (1) | AU3390284A (fr) |
BE (1) | BE900979A (fr) |
FR (1) | FR2554444B1 (fr) |
GB (1) | GB2149408A (fr) |
WO (1) | WO1985002189A1 (fr) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4973584A (en) * | 1989-03-09 | 1990-11-27 | Deluca Hector F | Novel 1α-hydroxyvitamin D2 epimer and derivatives |
US5194431A (en) * | 1992-07-08 | 1993-03-16 | Wisconsin Alumni Research Foundation | 24-cyclopropane vitamin D derivatives |
WO1993014763A1 (fr) * | 1992-01-29 | 1993-08-05 | Lunar Corporation | 1α-HYDROXY-24-EPI-VITAMINE D¿4? |
US5246925A (en) * | 1989-03-09 | 1993-09-21 | Wisconsin Alumni Research Foundation | 19-nor-vitamin D compounds for use in treating hyperparathyroidism |
US5260290A (en) * | 1990-02-14 | 1993-11-09 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
US5373004A (en) * | 1993-11-24 | 1994-12-13 | Wisconsin Alumni Research Foundation | 26,28-methylene-1α, 25-dihydroxyvitamin D2 compounds |
US5397775A (en) * | 1991-12-26 | 1995-03-14 | Wisconsin Alumni Research Foundation | 26,27-dimethylene-1α,25-dihydroxyvitamin D2 and 26,27-dimethylene-24-epi-1α,25-dihydroxyvitamin D2 and methods for preparing same |
US5484782A (en) * | 1993-11-03 | 1996-01-16 | Wisconsin Alumni Research Foundation | (E)-20(22)-dehydrovitamin D compounds |
US5561123A (en) * | 1989-03-09 | 1996-10-01 | Wisconsin Alumni Research Foundation | Method of treating proliferative skin disorders with 19-nor-vitamin D compounds |
US5716946A (en) * | 1996-02-13 | 1998-02-10 | Wisconsin Alumni Research Foundation | Multiple sclerosis treatment |
US5756783A (en) * | 1990-09-21 | 1998-05-26 | Bone Care International, Inc. | 1α-Hydroxy-24-EPI-vitamin D4 |
US6479474B2 (en) | 1999-07-08 | 2002-11-12 | Wisconsin Alumni Research Foundation | Dietary calcium as a supplement to vitamin D compound treatment of multiple sclerosis |
US20050070511A1 (en) * | 2003-08-20 | 2005-03-31 | Wisconsin Alumni Research Foundation | 2-methylene-19-nor-vitamin D2 compounds |
WO2010088304A1 (fr) | 2009-01-27 | 2010-08-05 | Cytotech Labs, Llc | Vitamines d3 et analogues de celles-ci pour soulagement des effets secondaires associés à une chimiothérapie |
WO2011019617A2 (fr) | 2009-08-14 | 2011-02-17 | Cytotech Labs, Llc | Vitamine d3 et ses analogues pour le traitement de l'alopécie |
WO2014194133A1 (fr) | 2013-05-29 | 2014-12-04 | Berg Llc | Prévention ou atténuation de l'alopécie induite par la chimiothérapie au moyen de vitamine d |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2608322B2 (ja) * | 1988-04-11 | 1997-05-07 | 日清製粉株式会社 | 1α,25‐ジヒドロキシビタミンD▲下2▼類の製造法 |
JP2645130B2 (ja) * | 1989-03-31 | 1997-08-25 | 日清製粉株式会社 | ステロイド誘導体 |
IN171449B (fr) * | 1990-02-14 | 1992-10-17 | Wisconsin Alumni Res Found | |
US5030772A (en) * | 1990-02-14 | 1991-07-09 | Deluca Hector F | Process for preparing vitamin D2 compounds and the corresponding 1 α-hydroxylated derivatives |
EP0664287B1 (fr) * | 1994-01-20 | 1998-07-15 | Duphar International Research B.V | Dérivés de vitamine D et leur procédé de préparation |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4225596A (en) * | 1978-10-13 | 1980-09-30 | Wisconsin Alumni Research Foundation | Method for treating calcium imbalance and improving calcium absorption in mammals |
US4260549A (en) * | 1979-05-21 | 1981-04-07 | Wisconsin Alumni Research Foundation | Process for preparing 1α-hydroxylated compounds |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3880894A (en) * | 1974-05-24 | 1975-04-29 | Wisconsin Alumni Res Found | 1,25-Dihydroxyergocalciferol |
FR2457282A1 (fr) * | 1979-05-23 | 1980-12-19 | Roussel Uclaf | Nouveau derive du 1a,25 dihydroxy cholecalciferol, son procede de preparation et son application comme medicament |
US4265822A (en) * | 1979-09-10 | 1981-05-05 | Wisconsin Alumni Research Foundation | Process for preparing 1-hydroxylated vitamin D compounds from 5,6-trans-vitamin D compounds |
US4338250A (en) * | 1981-04-27 | 1982-07-06 | Wisconsin Alumni Research Foundation | 1-Hydroxylation process |
IE58277B1 (en) * | 1983-05-09 | 1993-08-25 | Wisconsin Alumni Res Found | 1 , 25-dihydroxylated vitamin d2 compounds and intermediates in the preparation thereof |
-
1983
- 1983-11-07 US US06/549,047 patent/US4769181A/en not_active Expired - Lifetime
-
1984
- 1984-08-20 AU AU33902/84A patent/AU3390284A/en not_active Abandoned
- 1984-08-20 WO PCT/US1984/001334 patent/WO1985002189A1/fr unknown
- 1984-11-05 BE BE0/213952A patent/BE900979A/fr not_active IP Right Cessation
- 1984-11-06 FR FR8416894A patent/FR2554444B1/fr not_active Expired
- 1984-11-06 GB GB08428031A patent/GB2149408A/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4225596A (en) * | 1978-10-13 | 1980-09-30 | Wisconsin Alumni Research Foundation | Method for treating calcium imbalance and improving calcium absorption in mammals |
US4260549A (en) * | 1979-05-21 | 1981-04-07 | Wisconsin Alumni Research Foundation | Process for preparing 1α-hydroxylated compounds |
Cited By (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5561123A (en) * | 1989-03-09 | 1996-10-01 | Wisconsin Alumni Research Foundation | Method of treating proliferative skin disorders with 19-nor-vitamin D compounds |
US4973584A (en) * | 1989-03-09 | 1990-11-27 | Deluca Hector F | Novel 1α-hydroxyvitamin D2 epimer and derivatives |
US5710294A (en) * | 1989-03-09 | 1998-01-20 | Wisconsin Alumni Research Foundation | 19-nor vitamin D compounds |
US5246925A (en) * | 1989-03-09 | 1993-09-21 | Wisconsin Alumni Research Foundation | 19-nor-vitamin D compounds for use in treating hyperparathyroidism |
US5633241A (en) * | 1989-03-09 | 1997-05-27 | Wisconsin Alumni Research Foundation | 19-nor-vitamin D compounds |
US5342975A (en) * | 1989-03-09 | 1994-08-30 | Wisconsin Alumni Research Foundation | 19-nor-vitamin D compounds |
US5618805A (en) * | 1989-03-09 | 1997-04-08 | Wisconsin Alumni Research Foundation | 19-nor-vitamin D compounds |
US5587497A (en) * | 1989-03-09 | 1996-12-24 | Wisconsin Alumni Research Foundation | 19-nor-vitamin D compounds |
US5750746A (en) * | 1990-02-14 | 1998-05-12 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
US5260290A (en) * | 1990-02-14 | 1993-11-09 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
US5414098A (en) * | 1990-02-14 | 1995-05-09 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
US5532391A (en) * | 1990-02-14 | 1996-07-02 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
US5756783A (en) * | 1990-09-21 | 1998-05-26 | Bone Care International, Inc. | 1α-Hydroxy-24-EPI-vitamin D4 |
US5478955A (en) * | 1991-12-26 | 1995-12-26 | Wisconsin Alumni Research Foundation | 26,27-dimethylene-1α,25-dihydroxyvitamin D2 and 26, 27-dimethylene-24-epi-1α, 25-dihydroxyvitamin D2 and methods for preparing same |
US5494906A (en) * | 1991-12-26 | 1996-02-27 | Wisconsin Alumni Research Foundation | 26,27-dimethylene-1α,25-dihydroxyvitamin D2 and 26,27-dimethylene-24-EPI-1α,25-dihydroxyvitamin D2 and methods for preparing same |
US5397775A (en) * | 1991-12-26 | 1995-03-14 | Wisconsin Alumni Research Foundation | 26,27-dimethylene-1α,25-dihydroxyvitamin D2 and 26,27-dimethylene-24-epi-1α,25-dihydroxyvitamin D2 and methods for preparing same |
WO1993014763A1 (fr) * | 1992-01-29 | 1993-08-05 | Lunar Corporation | 1α-HYDROXY-24-EPI-VITAMINE D¿4? |
US5194431A (en) * | 1992-07-08 | 1993-03-16 | Wisconsin Alumni Research Foundation | 24-cyclopropane vitamin D derivatives |
US5565589A (en) * | 1993-11-03 | 1996-10-15 | Wisconsin Alumni Research Foundation | 17-formyl-5,6-trans-vitamin D compounds |
US5484782A (en) * | 1993-11-03 | 1996-01-16 | Wisconsin Alumni Research Foundation | (E)-20(22)-dehydrovitamin D compounds |
US5488044A (en) * | 1993-11-03 | 1996-01-30 | Wisconsin Alumni Research Foundation | Method of treating metabolic bone disease with (E)-20(22)-dehydrovitamin D compounds |
US5536828A (en) * | 1993-11-03 | 1996-07-16 | Wisconsin Alumni Research Foundation | (E)-20 (22)-dehydrodiels-alder compounds |
US5484781A (en) * | 1993-11-03 | 1996-01-16 | Wisconsin Alumni Research Foundation | (E)-20(22)-dehydrovitamin D compounds |
US5457217A (en) * | 1993-11-24 | 1995-10-10 | Wisconsin Alumni Research Foundation | 26,28-methylene-1α,25-dihydroxyvitamin D2 compounds |
US5373004A (en) * | 1993-11-24 | 1994-12-13 | Wisconsin Alumni Research Foundation | 26,28-methylene-1α, 25-dihydroxyvitamin D2 compounds |
US5716946A (en) * | 1996-02-13 | 1998-02-10 | Wisconsin Alumni Research Foundation | Multiple sclerosis treatment |
US6479474B2 (en) | 1999-07-08 | 2002-11-12 | Wisconsin Alumni Research Foundation | Dietary calcium as a supplement to vitamin D compound treatment of multiple sclerosis |
US20030207847A1 (en) * | 1999-07-08 | 2003-11-06 | Deluca Hector F. | Dietary calcium as a supplement to vitamin D compound treatment of multiple sclerosis |
US20050070511A1 (en) * | 2003-08-20 | 2005-03-31 | Wisconsin Alumni Research Foundation | 2-methylene-19-nor-vitamin D2 compounds |
US7232810B2 (en) * | 2003-08-20 | 2007-06-19 | Wisconsin Alumni Research Foundation | 2-methylene-19-nor-vitamin D2 compounds |
WO2010088304A1 (fr) | 2009-01-27 | 2010-08-05 | Cytotech Labs, Llc | Vitamines d3 et analogues de celles-ci pour soulagement des effets secondaires associés à une chimiothérapie |
WO2011019617A2 (fr) | 2009-08-14 | 2011-02-17 | Cytotech Labs, Llc | Vitamine d3 et ses analogues pour le traitement de l'alopécie |
EP3603646A1 (fr) | 2009-08-14 | 2020-02-05 | Berg LLC | Vitamine d3 et ses analogues pour le traitement de l'alopécie |
WO2014194133A1 (fr) | 2013-05-29 | 2014-12-04 | Berg Llc | Prévention ou atténuation de l'alopécie induite par la chimiothérapie au moyen de vitamine d |
Also Published As
Publication number | Publication date |
---|---|
FR2554444A1 (fr) | 1985-05-10 |
WO1985002189A1 (fr) | 1985-05-23 |
GB8428031D0 (en) | 1984-12-12 |
FR2554444B1 (fr) | 1987-11-06 |
GB2149408A (en) | 1985-06-12 |
BE900979A (fr) | 1985-03-01 |
AU3390284A (en) | 1985-06-03 |
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